Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication

The Mre11 nuclease is involved in early responses to DNA damage, often mediated by its role in DNA end processing. MRE11 mutations and aberrant expression are associated with carcinogenesis and cancer treatment outcomes. While, in recent years, progress has been made in understanding the role of Mre11 nuclease activities in DNA double-strand break repair, their role during replication has remained elusive. The nucleoside analog gemcitabine, widely used in cancer therapy, acts as a replication chain terminator; for a cell to survive treatment, gemcitabine needs to be removed from replicating DNA. Activities responsible for this removal have, so far, not been identified. We show that Mre11 3′ to 5′ exonuclease activity removes gemcitabine from nascent DNA during replication. This contributes to replication progression and gemcitabine resistance. We thus uncovered a replication-supporting role for Mre11 exonuclease activity, which is distinct from its previously reported detrimental role in uncontrolled resection in recombination-deficient cell

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types.

UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.The Breast Cancer Association Consortium (BCAC), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), and the Ovarian Cancer Association Consortium (OCAC) that contributed breast, prostate, and ovarian cancer data analyzed in this study were in part funded by Cancer Research UK [C1287/A10118 and C1287/A12014 for BCAC; C5047/A7357, C1287/A10118, C5047/A3354, C5047/A10692, and C16913/A6135 for PRACTICAL; and C490/A6187, C490/A10119, C490/A10124, C536/A13086, and C536/A6689 for OCAC]. Funding for the Collaborative Oncological Gene-environment Study (COGS) infrastructure came from: the European Community's Seventh Framework Programme under grant agreement number 223175 (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, and C8197/A16565), the US National Institutes of Health (CA128978) and the Post-Cancer GWAS Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative (1U19 CA148537, 1U19 CA148065, and 1U19 CA148112), the US Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund [with donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07)]. Additional financial support for contributing studies is documented under Supplementary Financial Support.This is the author accepted manuscript. The final version is available from the American Association for Cancer Research via http://dx.doi.org/10.1158/2159-8290.CD-15-122

Lika lön för lika arbete? : En studie av argumentationen kring folkskollärarnas lönedebatt i Svensk Läraretidning år 1906

Denna uppsats behandlar argumentationen kring folkskollärarnas lönedebatt som presenteras i Svenska läraretidning år 1906. Fokus ligger på argumentationen kring löneförslaget som tidningen presenterar, vilka argument som används och vilka delar tidningen tar upp. Detta har gjorts genom en argumentationsanalys utgående från Toulmins (1958) argumentationsmodell. Utifrån denna modell har jag systematiskt gått igenom argumentationen i tidningen. De olika aktörerna har delats in i olika grupper och deras argument har lyfts fram med de underliggande värderingar som ligger i grund för deras retorik. Slutsatserna därifrån presenteras i resultat och analysdelen. Diskussionen utgår från Connells (2003) teorier om genus som system och belyser tidningens argumentation utifrån manliga och kvinnliga egenskaper och samhälleliga strukturer. Det kan konstateras att merparten av argumentationen fokuserar på olika lön till kvinnor. Argumentationen utgår från att männen har rollen som familjeförsörjare och därmed har större ekonomiska behov. Man hänvisar också till andra samtida yrken där kvinnor har lägre ställning och sämre betalt än männen. Dock finns det motstånd mot den ojämna lönesättningen. Ett flertal folkskollärarinnor med petitioner presenteras men den mest framstående är Elsa Eschelsson som framför starka argument emot den olika lönen. Slutligen kan vi se hur folkskollärarkåren i detta forum står som enad för lika lön för lika arbete och utbildning medan det från samhällets håll i stort krävs att lärarinnorna skall få lägre lön.

Lika lön för lika arbete? : En studie av argumentationen kring folkskollärarnas lönedebatt i Svensk Läraretidning år 1906

Denna uppsats behandlar argumentationen kring folkskollärarnas lönedebatt som presenteras i Svenska läraretidning år 1906. Fokus ligger på argumentationen kring löneförslaget som tidningen presenterar, vilka argument som används och vilka delar tidningen tar upp. Detta har gjorts genom en argumentationsanalys utgående från Toulmins (1958) argumentationsmodell. Utifrån denna modell har jag systematiskt gått igenom argumentationen i tidningen. De olika aktörerna har delats in i olika grupper och deras argument har lyfts fram med de underliggande värderingar som ligger i grund för deras retorik. Slutsatserna därifrån presenteras i resultat och analysdelen. Diskussionen utgår från Connells (2003) teorier om genus som system och belyser tidningens argumentation utifrån manliga och kvinnliga egenskaper och samhälleliga strukturer. Det kan konstateras att merparten av argumentationen fokuserar på olika lön till kvinnor. Argumentationen utgår från att männen har rollen som familjeförsörjare och därmed har större ekonomiska behov. Man hänvisar också till andra samtida yrken där kvinnor har lägre ställning och sämre betalt än männen. Dock finns det motstånd mot den ojämna lönesättningen. Ett flertal folkskollärarinnor med petitioner presenteras men den mest framstående är Elsa Eschelsson som framför starka argument emot den olika lönen. Slutligen kan vi se hur folkskollärarkåren i detta forum står som enad för lika lön för lika arbete och utbildning medan det från samhällets håll i stort krävs att lärarinnorna skall få lägre lön.

Lika lön för lika arbete? : En studie av argumentationen kring folkskollärarnas lönedebatt i Svensk Läraretidning år 1906

Denna uppsats behandlar argumentationen kring folkskollärarnas lönedebatt som presenteras i Svenska läraretidning år 1906. Fokus ligger på argumentationen kring löneförslaget som tidningen presenterar, vilka argument som används och vilka delar tidningen tar upp. Detta har gjorts genom en argumentationsanalys utgående från Toulmins (1958) argumentationsmodell. Utifrån denna modell har jag systematiskt gått igenom argumentationen i tidningen. De olika aktörerna har delats in i olika grupper och deras argument har lyfts fram med de underliggande värderingar som ligger i grund för deras retorik. Slutsatserna därifrån presenteras i resultat och analysdelen. Diskussionen utgår från Connells (2003) teorier om genus som system och belyser tidningens argumentation utifrån manliga och kvinnliga egenskaper och samhälleliga strukturer. Det kan konstateras att merparten av argumentationen fokuserar på olika lön till kvinnor. Argumentationen utgår från att männen har rollen som familjeförsörjare och därmed har större ekonomiska behov. Man hänvisar också till andra samtida yrken där kvinnor har lägre ställning och sämre betalt än männen. Dock finns det motstånd mot den ojämna lönesättningen. Ett flertal folkskollärarinnor med petitioner presenteras men den mest framstående är Elsa Eschelsson som framför starka argument emot den olika lönen. Slutligen kan vi se hur folkskollärarkåren i detta forum står som enad för lika lön för lika arbete och utbildning medan det från samhällets håll i stort krävs att lärarinnorna skall få lägre lön.

Particle Flow Profiles From the Airways Measured by PExA Differ in Lung Transplant Recipients Who Develop Primary Graft Dysfunction

OBJECTIVES: Primary graft dysfunction is a severe form of acute lung injury and a major cause of early morbidity and mortality encountered after lung transplant.We used a customized PExA 2.0 instrument (PExA, Gothenburg, Sweden) to measure particle flow in exhaled air during mechanical ventilation in the intensive care unit. Our objective was to discover whether patients who developed primary graft dysfunction had different particle flow patterns from the airways. We used volume-controlled ventilation and pressure-controlled ventilation to see whether changes in particle patterns could be observed in both mechanical ventilation settings.MATERIALS AND METHODS: First, we investigated whether it was safe to use a customized PExA 2.0 in conjunction with mechanical ventilation. Next, 12 lung transplant patients were randomized to either daily volumecontrolled ventilation or pressure-controlled ventilation as the first mode of treatment until extubation.RESULTS: In our study group, 6 patients did not develop primary graft dysfunction and 6 developed primary graft dysfunction. Patients with primary graft dysfunction underwent mechanical ventilation significantly longer; they also showed a stepwise increase in particle count from day 0 until extubation. We observed no adverse events related to the PExA 2.0 device.CONCLUSIONS: This study suggests that the PExA 2.0 device is safe to use in conjunction with mechanical ventilation in the intensive care unit. Lung transplant patients who developed primary graft dysfunction showed a different particle profile from the airways before clinical signs of primary graft dysfunction developed. Online assessment of ventilation impact before presentation of tissue changes may allow realtime detection of primary graft dysfunction, thus preventing or reducing its effects

Releasing high positive end-expiratory pressure to a low level generates a pronounced increase in particle flow from the airways

Objectives: Detecting particle flow from the airways by a non-invasive analyzing technique might serve as an additional tool to monitor mechanical ventilation. In the present study, we used a customized particles in exhaled air (PExA) technique, which is an optical particle counter for the monitoring of particle flow in exhaled air. We studied particle flow while increasing and releasing positive end-expiratory pressure (PEEP). The aim of this study was to investigate the impact of different levels of PEEP on particle flow in exhaled air in an experimental setting. We hypothesized that gradually increasing PEEP will reduce the particle flow from the airways and releasing PEEP from a high level to a low level will result in increased particle flow. Methods: Five fully anesthetized domestic pigs received a gradual increase of PEEP from 5 cmH2O to a maximum of 25 cmH2O during volume-controlled ventilation. The particle count along with vital parameters and ventilator settings were collected continuously and measurements were taken after every increase in PEEP. The particle sizes measured were between 0.41 µm and 4.55 µm. Results: A significant increase in particle count was seen going from all levels of PEEP to release of PEEP. At a PEEP level of 15 cmH2O, there was a median particle count of 282 (154–710) compared to release of PEEP to a level of 5 cmH2O which led to a median particle count of 3754 (2437–10,606) (p < 0.009). A decrease in blood pressure was seen from baseline to all levels of PEEP and significantly so at a PEEP level of 20 cmH2O. Conclusions: In the present study, a significant increase in particle count was seen on releasing PEEP back to baseline compared to all levels of PEEP, while no changes were seen when gradually increasing PEEP. These findings further explore the significance of changes in particle flow and their part in pathophysiological processes within the lung

Particle flow rate from the airways as fingerprint diagnostics in mechanical ventilation in the intensive care unit : A randomised controlled study

Introduction Mechanical ventilation can be monitored by analysing particles in exhaled air as measured by particle flow rate (PFR). This could be a potential method of detecting ventilator-induced lung injury (VILI) before changes in conventional parameters can be detected. The aim of this study was to investigate PFR during different ventilation modes in patients without lung pathology. Method A prospective study was conducted on patients on mechanical ventilation in the cardiothoracic intensive care unit (ICU). A PExA 2.0 device was connected to the expiratory limb on the ventilator for continuous measurement of PFR in 30 patients randomised to either volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV) for 30 min including a recruitment manoeuvre. PFR measurements were continued as the patients were transitioned to pressure-regulated volume control (PRVC) and then pressure support ventilation (PSV) until extubation. Results PRVC resulted in significantly lower PFR, while those on PSV had the highest PFR. The distribution of particles differed significantly between the different ventilation modes. Conclusions Measuring PFR is safe after cardiac surgery in the ICU and may constitute a novel method of continuously monitoring the small airways in real time. A low PFR during mechanical ventilation may correlate to a gentle ventilation strategy. PFR increases as the patient transitions from controlled mechanical ventilation to autonomous breathing, which most likely occurs as recruitment by the diaphragm opens up more distal airways. Different ventilation modes resulted in unique particle patterns and could be used as a fingerprint for the different ventilation modes